Studies in animals suggest that the bispiperazinedione ICRF-187 can prevent the development of dose-related doxorubicin-induced cardiac toxicity. In a randomized trial in 92 women with advanced breast cancer, we compared treatment with fluorouracil, doxorubicin, and cyclophosphamide (FDC), given every 21 days, with the same regimen preceded by administration of ICRF-187 (FDC + ICRF-187). Patients were withdrawn from the study when cardiac toxicity developed or the cancer progressed. The mean cumulative dose of doxorubicin tolerated by patients withdrawn from study was 397.2 mg per square meter of body-surface area in the FDC group and 466.3 mg in the FDC + ICRF-187 group (no significant difference). Eleven patients on the FDC + ICRF-187 arm received cumulative doxorubicin doses above 600 mg per square meter, whereas one receiving FDC was able to remain in the study beyond this dose. Antitumor response rates were similar (FDC vs. FDC + ICRF-187, 3 vs. 4 complete responses; 17 vs. 17 partial responses; and 9.3 vs. 10.3 months to disease progression). Although myelosuppression was slightly greater in the FDC + ICRF-187 group, the incidence of fever, infections, alopecia, nausea and vomiting, or death due to toxicity did not differ between the groups. Cardiac toxicity was evaluated by clinical examination, determination of the left ventricular ejection fraction by multigated nuclear scans, and endomyocardial biopsy. In comparisons of the FDC group with the FDC + ICRF-187 group, clinical congestive heart failure was observed in 11 as compared with 2 patients; the mean decrease in the left ventricular ejection fraction was 7 vs. 1 percent when the cumulative dose of doxorubicin was 250 to 399 mg per square meter (P = 0.02), 16 vs. 1 percent at 400 to 499 mg (P = 0.001), and 16 vs. 3 percent at 500 to 599 mg (P = 0.003); and the Billingham biopsy score was 2 or more in 5 of 13 patients undergoing biopsy vs. none of 13 (P = 0.03). We conclude that ICRF-187 offers significant protection against cardiac toxicity caused by doxorubicin, without affecting the antitumor effect of doxorubicin or the incidence of noncardiac toxic reactions.

Background Left ventricular hypertrophy is a generalized adaptation to increased afterload, but the growth factors mediating this response have not been identified. To explore whether the hypertrophic response was associated with changes in local insulin-like growth factor-I (IGF-I) gene regulation, we examined the induction of the cardiac IGF-I gene in three models of systolic hypertension and resultant hypertrophy.Methods and Results The model systems were suprarenal aortic constriction, uninephrectomized spontaneously hypertensive rats (SHR), and uninephrectomized, deoxycorticosterone-treated, saline-fed rats (DOCA salt). Systolic blood pressure reached hypertensive levels at 3 to 4 weeks in all three systems. A differential increase in ventricular weight to body weight (hypertrophy) occurred at 3 weeks in the SHR and aortic constriction models and at 4 weeks in the DOCA salt model. Ventricular IGF-I mRNA was detected by solution hybridization/RNase protection assay. IGF-I mRNA levels

OBJECTIVE -The goal of this study was to determine whether treatment with an aldose reductase inhibitor (ARI) has beneficial effects on asymptomatic cardiac abnormalities in diabetic patients with neuropathy.RESEARCH DESIGN AND METHODS -Diabetic subjects with neuropathy (n ϭ 81) with either a low diastolic peak filling rate or impaired augmentation of left ventricular (LV) ejection fraction (LVEF) during maximal bicycle exercise were identified by gated radionuclide ventriculography. Coronary artery disease, left ventricular hypertrophy, and valvular heart disease were excluded by clinical evaluation, myocardial perfusion imaging, and echocardiography. Subjects were randomized to receive blinded treatment with either the placebo or the ARI zopolrestat 500 or 1,000 mg daily for 1 year. RESULTS-After 1 year of ARI treatment, there were increases in resting LVEF (P Ͻ 0.02), cardiac output (P Ͻ 0.03), LV stroke volume (P Ͻ 0.004), and exercise LVEF (P Ͻ 0.001). In placebo-treated subjects, there were decreases in exercise cardiac output (P Ͻ 0.03), stroke volume (P Ͻ 0.02), and end diastolic volume (P Ͻ 0.04). Exercise LVEF increased with ARI treatment independent of blood pressure, insulin use, or the presence of baseline abnormal heart rate variability. There was no change in resting diastolic filling rates in either group.CONCLUSIONS -Diabetic patients with neuropathy have LV abnormalities that can be stabilized and partially reversed by ARI treatment.

Abstract. Objective: To determine the effects of body temperature, ethanol use, electrolyte status, and acid-base status on the electrocardiograms (ECGs) of hypothermic patients. Methods: Prospective, two-year, observational study of patients presenting to an urban ED with temperature Յ95ЊF (Յ35ЊC). All patients had at least one ECG obtained. Electrocardiograms were interpreted by a cardiologist blinded to the patient's temperature. J-point elevations known as Osborn waves were defined as present if they were at least 1 mm in height in two consecutive complexes. Results: 100 ECGs were obtained in 43 patients. Presenting temperatures ranged between 74ЊF and 95ЊF (23.3ЊC-35ЊC). Initial rhythms included normal sinus (n = 34), atrial fibrillation (n = 8), and junctional (n = 1). Osborn waves were present in 37 of 43 initial ECGs. Of the six initial ECGs that did not have Osborn waves present, all were obtained in patients whose temperatures were Ն90ЊF (Ն32.2ЊC). For the entire group, the Osborn wave was significantly larger as temperature decreased (p = 0.0001, r = Ϫ0.441). The correlation between temperature and size of the Osborn wave was strongest in six patients with four or more ECGs (range r = Ϫ0.644 to r = Ϫ0.956, p = 0.001). No correlation could be demonstrated between the height of the Osborn waves and the serum electrolytes, including sodium, chloride, potassium, bicarbonate, BUN, creatinine, glucose, anion gap, and blood ethanol levels. Conclusions: The presence and size of the Osborn waves in hypothermic patients appear to be a function of temperature. The magnitude of the Osborn waves is inversely correlated with the temperature. Key words: hypothermia, electrocardiograph; Osborn waves. AC-ADEMIC EMERGENCY MEDICINE 1999; 6:1121-1126 T HE EFFECTS of hypothermia on cardiac conduction were first described in 1892.1 Since then, observations of the physiologic changes that occur with cooling of the heart have been reported in animals 2-14 and in humans undergoing craniotomy for subarachnoid hemorrhage, 15 surgery for cardiac anomalies, [16][17][18][19] and anti-cancer therapy. 20,21The first observation of the changes in the electrocardiogram (ECG) in a patient with unintentional hypothermia was reported in 1938. 22 In the following study, the changes in the ECGs of patients with unintentional hypothermia presenting to a large urban hospital ED are described, and the relationship of these changes to common laboratory parameters are analyzed. A review of the literature focuses on the development of the understanding of the effects of cold on the electrical conduction system of the heart and the resultant physiologic and ECG alterations. METHODSStudy Design. This was a prospective, two-year observational study of hypothermia patients presenting to an urban ED. The study was approved by the institutional review boards of New York University School of Medicine, Bellevue Hospital, and the New York City Health and Hospital Corporation.Study Setting and Population. For the purposes of this study, patients were sele...